US7847041B2 - Cobalt-catalyzed asymmetric cyclopropanation of electron-deficient olefins - Google Patents
Cobalt-catalyzed asymmetric cyclopropanation of electron-deficient olefins Download PDFInfo
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- US7847041B2 US7847041B2 US12/205,373 US20537308A US7847041B2 US 7847041 B2 US7847041 B2 US 7847041B2 US 20537308 A US20537308 A US 20537308A US 7847041 B2 US7847041 B2 US 7847041B2
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C67/347—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by addition to unsaturated carbon-to-carbon bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
Definitions
- the present invention generally relates to metal-catalyzed cyclopropanation of olefins. More particularly, the present invention relates to a process for asymmetric cyclopropanation of electron-deficient olefins using a cobalt porphyrin complex.
- the present invention provides for a general and efficient catalytic system for asymmetric cyclopropanation of electron-deficient olefins.
- the cobalt (II) complex of the D 2 -symmetric chiral porphyrin can cyclopropanate a wide range of electron-deficient olefins, forming the corresponding electrophilic cyclopropane derivatives in high yields and selectivities.
- the present invention is further directed to a process for asymmetric cyclopropanation of an olefin wherein at least one of the olefinic carbon atoms possesses an electron withdrawing group.
- the process comprises treating the olefin with a diazo ester in the presence of a chiral porphyrin complex.
- aryl or “ar” as used herein alone or as part of another group denote optionally substituted homocyclic aromatic groups, preferably monocyclic or bicyclic groups containing from 6 to 12 carbons in the ring portion, such as phenyl, biphenyl, naphthyl, substituted phenyl, substituted biphenyl or substituted naphthyl. Phenyl and substituted phenyl are the more preferred aryl.
- the substituted aryl groups described herein may have, as substituents, any of the substituents identified as substituted hydrocarbyl substituents.
- diazo or “azo” as used herein describe an organic compound with two linked nitrogen compounds. These moieties include without limitation diazomethane, ethyl diazoacetate, and t-butyl diazoacetate.
- compounds containing an ethylenic bond commonly known as olefins, possessing an electron-deficient substituent on at least one of the ethylenic carbons (also sometimes referred to as an olefinic carbon) are cyclopropanated with a diazo reagent in the presence of a cobalt porphyrin complex.
- the metal porphyrin catalyzed process proceeds relatively efficiently under relatively mild and neutral conditions, in a one-pot fashion, with olefins as limiting reagents and without the need for slow-addition of diazo reagents.
- the olefin corresponds to Formula 1:
- R 1 is a substituent of the ⁇ -carbon of the ethylenic bond
- R 2 and R 3 are substituents of the ⁇ -carbon of the ethylenic bond.
- R 1 is hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclo and R 2 and R 3 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclo, or an electron withdrawing group.
- R 1 is hydrogen.
- R 1 is alkyl or substituted alkyl.
- R 2 is hydrogen.
- R 2 is alkyl or substituted alkyl.
- R 3 is hydrogen.
- the olefin corresponds to Formula 1 and one of R 2 and R 3 is an electron withdrawing group, the olefin corresponds to Formula 1-trans or 1-cis, respectively:
- EWG 1 and EWG 2 are electron withdrawing groups and are the same or are different, R 1 is a substituent of the ⁇ -carbon of the ethylenic bond, and R 2 and R 3 are substituents of the ⁇ -carbon of the ethylenic bond.
- R 1 , R 2 and R 3 are preferably independently hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo.
- EWG is an electron withdrawing group
- R 2 and R 3 is hydrogen
- the olefin corresponds to Formula 2-trans or Formula 2-cis:
- EWG 1 is an electron withdrawing group
- R 2 and R 3 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclo, or EWG 2
- EWG 2 is an electron withdrawing group
- EWG 1 and EWG 2 are the same or are different.
- the olefin corresponds to Formula 1 and R 1 , R 2 and R 3 are hydrogen. Olefins having this substitution pattern are depicted by Formula 3:
- EWG is an electron withdrawing group
- the olefin's electron withdrawing group(s) for example, EWG, EWG 1 or EWG 2 as depicted in Formula 1, Formula 2, Formula 2-trans, Formula 2-cis, or Formula 3, is any substituent that draws electrons away from the ethylenic bond.
- Exemplary electron withdrawing groups include hydroxy, alkoxy, mercapto, halogens, carbonyls, sulfonyls, nitrile, quaternary amines, nitro, trihalomethyl, imine, amidine, oxime, thioketone, thioester, or thioamide.
- the electron withdrawing group(s) is/are hydroxy, alkoxy, mercapto, halogen, carbonyl, sulfonyl, nitrile, quaternary amine, nitro, or trihalomethyl. In another embodiment, the electron withdrawing group(s) is/are halogen, carbonyl, nitrile, quaternary amine, nitro, or trihalomethyl. In another embodiment, the electron withdrawing group(s) is/are halogen, carbonyl, nitrile, nitro, or trihalomethyl. When the electron withdrawing group is alkoxy, it generally corresponds to the formula —OR where R is hydrocarbyl, substituted hydrocarbyl, or heterocyclo.
- the electron withdrawing group When the electron withdrawing group is mercapto, it generally corresponds to the formula —SR where R is hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo.
- the electron withdrawing group When the electron withdrawing group is a halogen atom, the electron withdrawing group may be fluoro, chloro, bromo, or iodo; typically, it will be fluoro or chloro.
- the electron withdrawing group when it is a carbonyl, it may be an aldehyde (—C(O)H), ketone (—C(O)R), ester (—C(O)OR), acid (—C(O)OH), acid halide (—C(O)X), amide (—C(O)NR a R b ), or anhydride (—C(O)OC(O)R) where R is hydrocarbyl, substituted hydrocarbyl or heterocyclo, R a and R b are independently hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo, and X is a halogen atom.
- the electron withdrawing group When the electron withdrawing group is a sulfonyl, it may be an acid (—SO 3 H) or a derivative thereof (—SO 2 R) where R is hydrocarbyl, substituted hydrocarbyl or heterocyclo.
- R When the electron withdrawing group is a quaternary amine, it generally corresponds to the formula —N + R a R b R c where R a , R b and R c are independently hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo.
- the electron withdrawing group When the electron withdrawing group is a trihalomethyl, it is preferably trifluoromethyl or trichloromethyl.
- X may be chloro or fluoro, preferably fluoro.
- R may be alkyl.
- R a and R b may independently be hydrogen or alkyl.
- ⁇ , ⁇ -unsaturated carbonyl compounds and ⁇ , ⁇ -unsaturated nitriles are preferred olefins for cyclopropanation.
- the olefin's electron withdrawing group(s) for example, EWG, EWG 1 or EWG 2 as depicted in Formula 1, Formula 2, Formula 2-trans, Formula 2-cis, or Formula 3, is/are a carbonyl or a nitrile.
- the electron withdrawing group(s) is/are a halide, aldehyde, ketone, ester, carboxylic acid, amide, acyl chloride, trifluoromethyl, nitrile, sulfonic acid, ammonia, amine, or a nitro group.
- the electron withdrawing group(s) correspond to one of the following chemical structures: —X, —C(O)H, —C(O)R, —C(O)OR, —C(O)OH, —C(O)X, —C(X) 3 , —CN, —SO 3 H, —N + H 3 , —N + R 3 , or —N + O 2 where R is hydrocarbyl, substituted hydrocarbyl or heterocyclo and X is halogen.
- the olefin is cyclopropanated with a carbene.
- the carbene precursor is a diazo reagent (also sometimes referred to herein as a diazo compound) wherein the carbene is generated by the removal of N 2 as nitrogen gas from the solution.
- the carbene precursor is a diazo carbonyl compound.
- the carbene precursor is a diazo ester.
- the diazo compound is selected from the group consisting of diazo ethylacetate, diazo-t-butylacetate, 2,6-di-tert-butyl-4-methylphenyl diazoacetate, methyl phenyldiazoacetate, ethyl diazoacetacetate, diethyl diazomalonate, and trimethylsilyldiazomethane.
- the diazo compound is selected from one of diazo ethylacetate and diazo t-butylacetate.
- the diazo compound has the formula N 2 CHC(O)OR 10 where R 10 is hydrocarbyl, substituted hydrocarbyl or heterocyclo.
- the diazo compound has the formula N 2 CHC(O)OR 10 where R 10 is alkyl, aryl or alkaryl, more lower alkyl or aryl.
- R 10 is alkyl, aryl or alkaryl, more lower alkyl or aryl.
- Other exemplary diazo acetates include 2,3,4-trimethyl-3-pentyl diazoacetate, menthyl diazoacetate, 2,5-dimethyl-4-buten-1-yl diazoacetate, 3-(diazoacetyl)amino propionate, and (diazoacetyl)amino acetate.
- an olefin is converted to a cyclopropane as illustrated in Reaction Scheme A:
- [Co(Por)] is a cobalt porphyrin complex
- R 1 is hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclo
- R 2 , and R 3 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclo, or EWG 2
- R 5 and R 6 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclo, provided one of R 5 and R 6 is carbonyl
- EWG and EWG 2 are independently an electron-withdrawing group.
- one of R 5 and R 6 is hydrogen and the other is carbonyl.
- one of R 5 and R 6 is hydrogen and the other is an ester (—C(O)OR wherein R is hydrocarbyl, substituted hydrocarbyl, or heterocyclo).
- [Co(Por)] is a cobalt porphyrin complex
- R 1 is hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclo
- R 2 , and R 3 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclo, or EWG 2
- R 10 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo
- EWG and EWG 2 are independently an electron-withdrawing group.
- [Co(Por)] is a cobalt porphyrin complex
- R 1 is hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclo
- R 2 , and R 3 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclo, or EWG 2
- R 10 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo
- R 11 is hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclo, —NR a R b , —OR a , or —OC(O)OC(O)R a
- R a and R b are independently hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo
- EWG and EWG 2 are independently an electron-withdrawing group.
- R 1 is hydrogen.
- R 1 is hydrogen and R 2 and R 3 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo.
- R 1 is hydrogen and one of R 2 and R 3 is hydrogen.
- R 1 is hydrogen
- one of R 2 and R 3 is hydrogen
- the other of R 2 and R 3 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo.
- R 10 may be alkyl, typically lower alkyl.
- each of the ethylenic carbons possesses an electron withdrawing group and the cyclopropanation reaction proceeds as depicted in Reaction Scheme 4 or 5:
- R 1 is hydrogen and R 2 or R 3 is hydrogen.
- R 1 is hydrogen, and R 2 or R 3 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo.
- R 10 may be alkyl, typically lower alkyl.
- the porphyrin with which cobalt is complexed may be any of a wide range of porphyrins known in the art. Exemplary porphyrins are described in U.S. Patent Publication Nos. 2005/0124596 and 2006/0030718 and U.S. Pat. No. 6,951,934 (each of which is incorporated herein by reference, in its entirety). Exemplary porphyrins are also described in Chen et al., Bromoporphyrins as Versatile Synthons for Modular Construction of Chiral Porphyrins: Cobalt-Catalyzed Highly Enantioselective and Diastereoselective Cyclopropanation ( J. Am. Chem. Soc. 2004), which is incorporated herein by reference in its entirety.
- the cobalt porphyrin complex is a cobalt (II) porphyrin complex.
- the cobalt porphyrin complex is a D 2 -symmetric chiral porphyrin complex corresponding to the following structure
- each Z 1 , Z 2 , Z 3 , Z 4 , Z 5 and Z 6 are each independently selected from the group consisting of X, H, alkyl, substituted alkyls, arylalkyls, aryls and substituted aryls; and X is selected from the group consisting of halogen, triflouromethanesulfonate (OTf), haloaryl and haloalkyl.
- Z 2 , Z 3 , Z 4 and Z 5 are hydrogen
- Z 1 is a substituted phenyl
- Z 6 is substituted phenyl
- Z 1 and Z 6 are different.
- cobalt (II) porphyrins include the following:
- the cyclopropanation reaction could be carried out efficiently at room temperature in a one-pot fashion with olefins as limiting reagents and would not require the slow-addition of ester reagents. Additionally, the cyclopropanation reaction may be operated with relatively low catalyst loading, in a solvent such as toluene, chlorobenzene, tetrahydrofuran (THF), dichloromethane, or acetonitrile.
- a solvent such as toluene, chlorobenzene, tetrahydrofuran (THF), dichloromethane, or acetonitrile.
- the enantioselectivity and diastereoselectivity can be influenced, at least in part, by the selection of the solvent.
- the solvent is chlorobenzene, which was found to give the desired cyclopropane in the highest yield and with the best enantioselectivity as well as diastereoselectivity.
- acrylamide as well as its mono- and di-substituted derivatives were also suitable substrates, providing the corresponding 1,2-cyclopropaneamidoesters with good to high yields and excellent selectivities (Table 1, entries 6-10).
- the amido functional groups were well tolerated; no N—H insertion products were observed.
- Alkenes bearing carbonyl and cyano groups such as acrylketones and acrylonitriles were fully compatible with the catalytic system as well.
- the resulting 1,2-cyclopropaneketoesters (Table 1, entries 11-15) and 1,2-cyclopropane cyanoesters (Table 1, entries 16-19) could be synthesized in high yields and high selectivities.
- [Co(1)] is an effective catalyst for asymmetric cyclopropanation of various electron-deficient olefins under mild conditions, forming synthetically valuable electrophilic cyclopropane derivatives in high yields and high stereoselectivities. Together with its high reactivity and selectivity toward styrene derivatives shown previously, [Co(1)] may be considered one of the most selective catalysts for asymmetric cyclopropanation of both electron-sufficient and electron-deficient olefins with diazoacetates. (Lebel et al., Chem. Rev. 2003, 103, 977; Davies H. M. L., Antoulinakis E., Org. React.
- tert-Butyl 2-aminocarbonyl-cyclopropanecarboxylate (Entry 7, Table 1) was synthesized from acrylamide with t-BDA.
- trans-isomer 1 H NMR (300 MHz, CDC1 3 ): ⁇ 6.08 (br, 2H), 2.04-2.10 (m, 1H), 1.93-1.99 (m, 1H), 1.45 (s, 9H), 1.32-1.41 (m, 1H), 1.26-1.30 (m, 1H).
- tert-Butyl 2-dimethylaminocarbonyl-cyclopropanecarboxylate (Entry 9, Table 1) was synthesized from N,N-dimethylacrylamide with t-BDA.
- trans-isomer 1 H NMR (300 MHz, CDC1 3 ): ⁇ 3.17 (s, 3H), 2.97 (s, 3H), 2.22-2.28 (m, 1H), 2.07-2.13 (m, 1H), 1.45 (s, 9H), 1.35-1.40 (m, 1H), 1.26-1.32 (m, 1H).
- tert-Butyl 2-isopropylaminocarbonyl-cyclopropanecarboxylate (Entry 10, Table 1) was synthesized from N-isopropylacylamide with t-BDA.
- tert-Butyl 2-propionyl-cyclopropanecarboxylate (Entry 12, Table 1) was synthesized from ethyl vinyl ketone with t-BDA.
- 13 C NMR (75 MHz, CDC1 3 ): ⁇ 208.3, 171.2, 81.1, 37.0, 28.5, 28.0, 25.0, 16.9, 7.6.
- Ethyl 2-hexanoyl-cyclopropanecarboxylate (Entry 13, Table 1) was synthesized from 1-octen-3-one with EDA.
- tert-Butyl 2-hexanoyl-cyclopropanecarboxylate (Entry 14, Table 1) was synthesized from 1-octen-3-one with t-BDA.
- tert-Butyl 2-acetyl-2-methyl-cyclopropanecarboxylate (Entry 15, Table 1) was synthesized from 3-methyl-3-buten-2-one with t-BDA.
- trans-isomer 1 H NMR (300 MHz, CDC1 3 ): ⁇ 2.20-2.25 (m, 1H), 2.21 (s, 3H), 1.48 (s, 3H), 1.42-1.50 (m, 1H), 1.46 (s, 9H), 1.24-1.27 (m, 1H).
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Abstract
Description
wherein EWG is an electron withdrawing group, R1 is a substituent of the α-carbon of the ethylenic bond, and R2 and R3 are substituents of the β-carbon of the ethylenic bond. Preferably, R1 is hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclo and R2 and R3 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclo, or an electron withdrawing group. In one embodiment, R1 is hydrogen. In another embodiment, R1 is alkyl or substituted alkyl. In one embodiment, R2 is hydrogen. In another embodiment, R2 is alkyl or substituted alkyl. In one embodiment, R3 is hydrogen. In another embodiment, R3 is alkyl or substituted alkyl. In one embodiment, at least one of R1, R2 and R3 is hydrogen and the other two are alkyl or substituted alkyl. In one embodiment, at least two of R1, R2 and R3 are hydrogen and the other is alkyl or substituted alkyl.
wherein EWG1 and EWG2 are electron withdrawing groups and are the same or are different, R1 is a substituent of the α-carbon of the ethylenic bond, and R2 and R3 are substituents of the β-carbon of the ethylenic bond. In this embodiment, R1, R2 and R3 are preferably independently hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo.
wherein EWG is an electron withdrawing group, and at least one of R2 and R3 is hydrogen. When one of R2 and R3 is other than hydrogen, the olefin corresponds to Formula 2-trans or Formula 2-cis:
wherein EWG1 is an electron withdrawing group, R2 and R3 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclo, or EWG2, EWG2 is an electron withdrawing group, and EWG1 and EWG2 are the same or are different.
wherein [Co(Por)] is a cobalt porphyrin complex, R1 is hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclo, R2, and R3 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclo, or EWG2, R5 and R6 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclo, provided one of R5 and R6 is carbonyl, and EWG and EWG2 are independently an electron-withdrawing group. In a preferred embodiment, one of R5 and R6 is hydrogen and the other is carbonyl. In a more preferred embodiment, one of R5 and R6 is hydrogen and the other is an ester (—C(O)OR wherein R is hydrocarbyl, substituted hydrocarbyl, or heterocyclo).
wherein [Co(Por)] is a cobalt porphyrin complex; R1 is hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclo, R2, and R3 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclo, or EWG2, R10 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo, and EWG and EWG2 are independently an electron-withdrawing group.
wherein [Co(Por)] is a cobalt porphyrin complex, R1 is hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclo, R2, and R3 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclo, or EWG2, R10 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo, R11 is hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclo, —NRaRb, —ORa, or —OC(O)OC(O)Ra, Ra and Rb are independently hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo, and EWG and EWG2 are independently an electron-withdrawing group. In one such embodiment in which the cyclopropanation reaction proceeds as set forth as depicted in Reaction Scheme 2 or 3, R1 is hydrogen. In another embodiment in which the cyclopropanation reaction proceeds as depicted in Reaction Scheme 2 or 3, R1 is hydrogen and R2 and R3 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo. In another embodiment in which the cyclopropanation reaction proceeds as depicted in Reaction Scheme 2 or 3, R1 is hydrogen and one of R2 and R3 is hydrogen. In another embodiment in which the cyclopropanation reaction proceeds as depicted in Reaction Scheme 2 or 3, R1 is hydrogen, one of R2 and R3 is hydrogen, and the other of R2 and R3 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo. In a further embodiment, R10 may be alkyl, typically lower alkyl.
wherein [Co(Por)] is a cobalt porphyrin complex, R1, R2, and R3 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclo, R10 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo, and EWG1 and EWG2 are independently an electron-withdrawing group. In one such embodiment in which the cyclopropanation reaction proceeds as set forth as depicted in Reaction Scheme 4 or 5, R1 is hydrogen. In another embodiment in which the cyclopropanation reaction proceeds as set forth as depicted in Reaction Scheme 4 or 5, R1 is hydrogen and R2 and R3 are hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo. In another embodiment in which the cyclopropanation reaction proceeds as depicted in Reaction Scheme 4 or 5, R1 is hydrogen and R2 or R3 is hydrogen. In another embodiment in which the cyclopropanation reaction proceeds as depicted in Reaction Scheme 4 or 5, R1 is hydrogen, and R2 or R3 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo. In a further embodiment, R10 may be alkyl, typically lower alkyl.
wherein each Z1, Z2, Z3, Z4, Z5 and Z6 are each independently selected from the group consisting of X, H, alkyl, substituted alkyls, arylalkyls, aryls and substituted aryls; and X is selected from the group consisting of halogen, triflouromethanesulfonate (OTf), haloaryl and haloalkyl. In a preferred embodiment, Z2, Z3, Z4 and Z5 are hydrogen, Z1 is a substituted phenyl, and Z6 is substituted phenyl, and Z1 and Z6 are different. In one particularly preferred embodiment, Z2, Z3, Z4 and Z5 are hydrogen, Z1 is substituted phenyl, and Z6 is substituted phenyl and Z1 and Z6 are different and the porphyrin is a chiral porphyrin. In one even further preferred embodiment, Z2, Z3, Z4 and Z5 are hydrogen, Z1 is substituted phenyl, and Z6 is substituted phenyl and Z1 and Z6 are different and the porphyrin has D2-symmetry.
Previous studies on asymmetric cyclopropanation of styrene derivatives revealed that a [Co(1)]-based system seemed insensitive to substrate electronics. (Huang et al, J. Org. Chem. 2003, 68, 8179; Chen et al., J. Am. Chem. Soc. 2004, 126, 14718; and Chen Y., Zhang, X. P., J. Org. Chem. 2007, 72, 5931.) Even the extremely electron-deficient pentafluorostyrene could be cyclopropanated. (Chen Y., Zhang, X. P., J. Org. Chem. 2007, 72, 5931.) This result prompted us to evaluate the catalytic reactivity of [Co(1)] toward more challenging substrates such as electron-deficient non-styrene olefins (Table 1). Under the one-pot protocol where olefins are the limiting reagent, using 1 mol % [Co(1)] in the presence of 0.5 equivalents of DMAP could effectively cyclopropanate both acrylates and methacrylates with EDA or tert-butyl diazoacetate (t-BDA) at room temperature in toluene, forming the corresponding 1,2-cyclopropanediesters in good yields and high diastereo-as well as enantio-selectivities (Table 1, entries 1-5). Under the same conditions, acrylamide as well as its mono- and di-substituted derivatives were also suitable substrates, providing the corresponding 1,2-cyclopropaneamidoesters with good to high yields and excellent selectivities (Table 1, entries 6-10). The amido functional groups were well tolerated; no N—H insertion products were observed. Alkenes bearing carbonyl and cyano groups such as acrylketones and acrylonitriles were fully compatible with the catalytic system as well. In most of the cases, the resulting 1,2-cyclopropaneketoesters (Table 1, entries 11-15) and 1,2-cyclopropane cyanoesters (Table 1, entries 16-19) could be synthesized in high yields and high selectivities. As the best example, cyclopropanation of 1-octen-3-one with t-BDA resulted in the formation of the desired trans-1,2-cyclopropaneketoester in 94% yield, 98% de, and 96% ee (Table 1, entry 14). Diethyl maleate could also be successfully cyclopropanated to produce the 1,2,3-cyclopropanetriester solely as the α,α,β-isomer, albeit in a lower yield (Table 1, entry 20).
TABLE 1 |
Diastereoselective and Enantioselective Cyclopropanation of Electron- |
Deficient Olefins Catalyzed by [Co(1)].a |
entry | alkene | diazo | product | yield (%)c | t:cd | ee (%)e |
1 1Ab |
|
EDA |
|
78 95 | 98:02 97:03 | 80g 81g |
2 2Ab |
|
t-BDA |
|
72 92 | 99:01 99:01 | 90 91 |
3 3Ab |
|
t-BDA |
|
62 88 | 98:02 97:03 | 84 80 |
4 |
|
EDA |
|
73 | 95:05 | 61 |
5 5Ab |
|
t-BDA |
|
62 90 | 93:07 93:07 | 84 83 |
6 6Ab |
|
EDA |
|
51 81 | 99:01 99:01 | 88 90 |
7 7Ab |
|
t-BDA |
|
66 77 | 99:01 99:01 | 97 97 |
8 |
|
EDA |
|
85 | 99:01 | 77 |
9 |
|
t-BDA |
|
86 | 99:01 | 96 |
10 10Ab |
|
t-BDA |
|
44 96 | 99:01 99:01 | 97 96 |
11 |
|
EDA |
|
89 | 96:04 | 80 |
12 |
|
t-BDA |
|
81 | 99:01 | 94 |
13 |
|
EDA |
|
92 | 98:02 | 79 |
14 |
|
t-BDA |
|
94 | 99:01 | 96 |
15 15Ab |
|
t-BDA |
|
40 84 | 98:02 97:03 | 90 87 |
16 |
|
EDA |
|
83 | 72:28 | 73 |
17 |
|
t-BDA |
|
83 | 76:24 | 93 |
18 18Ab |
|
EDA |
|
77 93 | 69:31 69:31 | 84 81 |
19 |
|
t-BDA |
|
87 | 62:38 | 95 |
20 20Ab |
|
EDA |
|
37 94 | >99:1f >99:1f | — — |
aPerformed in toluene at RT for 20 h using 1 mol % [Co(1)] under N2 with 1.0 equiv of alkene and 1.2 equiv of EDA or t-BDA in the presence of 0.5 equiv of DMAP. [alkene] = 0.25 M. | ||||||
bPerformed in chlorobenzene. | ||||||
cIsolated yields. | ||||||
dDetermined by GC. | ||||||
eDetermined by GC or HPLC on chiral stationary phases. | ||||||
fOnly the □.□.□-isomer was observed. | ||||||
g(−)-[1R,2R] absolute configuration determined by optical rotation. |
TABLE 2 |
Solvent Effect in [Co(1)]-Catalyzed Diastereoselective and |
Enantioselective Cyclopropanation of Electron-Deficient Olefins.a |
|
entry | solvent | yield (%)b | trans:cisc | ee (%)d |
1 | MeC6H5 | 72 | 99:01 | 90 |
2 | ClC6H5 | 92 | 99:01 | 91 |
3 | THF | 29 | 88:12 | 76 |
4 | CH2Cl2 | 61 | 99:01 | 85 |
5 | CH3CN | 58 | 96:04 | 84 |
aPerformed at room temperature for 20 h using 1 mol % [Co(1)] under N2 with 1.0 equiv of alkene and 1.2 equiv of t-BDA in the presence of 0.5 equiv of DMAP. [alkene] = 0.25 M. | ||||
bIsolated yields. | ||||
cThe trans:cis ratios were determined by GC. | ||||
dThe ee of trans isomer was determined by chiral GC or chiral HPLC. |
(−)-(1R,2R)-diethyl 1,2-cyclopropanedicarboxylate (Csuk R., von Scholz Y., Tetrahedron 1994, 50, 10431; Jeromin et al., Ger. Offen. 2006.) (Entry 1, Table 1) was synthesized from ethyl acrylate with EDA. trans-isomer: [α]27 365=−452.1 (c=0.42, CHCl3). 1H NMR (300 MHz, CDC13): δ4.15 (q, J=7.2 Hz, 4H), 2.13-2.18 (m, 2H), 1.40-1.45 (m, 2H), 1.28 (t, J=7.2 Hz, 6H). 13C NMR (75 MHz, CDC13): δ171.8, 61.0, 22.3, 15.3, 14.1. IR (film, cm−1): 1728 (C═O). HRMS (ESI): Calcd. for C9H15O4 ([M+H]+) m/z 187.0970, Found 187.0964. GC analysis: Chiraldex G-TA (Temp program: initial temp=50° C., 2.00° C./min, final temp=180° C., final time=10.00 min) trans-isomer: tminor=30.46 min, tmajor=30.74 min.
tert-Butyl ethyl 1,2-cyclopropanedicarboxylate (Bonavent et al., Bull. Soc. Chim. Fr. 1964, 10, 2462.) (Entry 2, Table 1) was synthesized from tert-butyl acrylate with EDA or from ethyl acrylate with t-BDA. trans-isomer: 1H NMR (300 MHz, CDC13): δ4.15 (q, J=7.2 Hz, 2H), 2.06-2.11 (m, 2H), 1.45 (s, 9H), 1.34-1.39 (m, 2H), 1.28 (t, J=7.2 Hz, 3H). 13C NMR (75 MHz, CDC13): δ172.0, 170.9, 81.2, 61.0, 28.0, 23.3, 22.0, 15.2, 14.1. IR (film, cm−1): 1725 (C═O). HRMS (ESI): Calcd. for C11H22O4N ([M+NH4]+) m/z 232.1549, Found 232.1545. GC analysis: CP-Chirasil-Dex CB (Temp program: initial temp=50° C., Rate1: 10.00° C./min, max temp=100° C.; Rate2: 2.00° C./min, max temp=140° C.; Rate3: 10.00° C./min, max temp=200° C.; final time=0.00 min) trans-isomer: tminor=21.18 min, tmajor=21.36 min.
Di-tert-butyl 1,2-cyclopropanedicarboxylate (Artaud et al., Acad. Sci., Ser. IIc: Chim. 1976, 283, 503.) (Entry 3, Table 1) was synthesized from tert-butyl acrylate with t-BDA. trans-isomer: 1H NMR (300 MHz, CDC13): δ1.98-2.02 (m, 2H), 1.45 (s, 18H), 1.26-1.31 (m, 2H). 13C NMR (75 MHz, CDC13): δ171.1, 81.0, 28.0, 23.1, 15.2. IR (film, cm−1): 1724 (C═O). HRMS (ESI): Calcd. for C13H26O4N ([M+NH4]+) m/z 260.1862, Found 260.1856. GC analysis: CP-Chirasil-Dex CB (Temp program: initial temp=50° C., 10.00° C./min, final temp=200° C., final time=10.00 min) trans-isomer: tminor=14.54 min, tmajor=14.59 min.
Ethyl methyl 1-methyl-1,2-cyclopropanedicarboxylate (Doyle et al., J. Org. Chem. 1982, 47, 4059.) (Entry 4, Table 1) was synthesized from methyl methacrylate with EDA. trans-isomer: 1H NMR (300 MHz, CDC13): δ4.17 (q, J=7.2 Hz, 2H), 3.70 (s, 3H), 2.30-2.36 (m, 1H), 1.55-1.59 (m, 1H), 1.40 (s, 3H), 1.31-1.34 (m, 1H), 1.28 (t, J=7.2 Hz, 3H). 13C NMR (75 MHz, CDC13): δ174.0 170.3, 60.9, 52.3, 27.9, 26.8, 20.9, 14.2, 13.0. IR (film, cm−1): 1727 (C═O). HRMS (ESI): Calcd. for C9H18O4N ([M+NH4]+) m/z 204.1236, Found 240.1229. GC analysis: CP-Chirasil-Dex CB (Temp program: initial temp=50° C., Rate1: 3.00° C./min, max temp=100° C.; Rate2: 2.00° C./min, max temp=130° C.; Rate3: 10.00° C./min, max temp=200° C.; final time=5.00 min) trans-isomer: tminor=25.36 min, tmajor=25.47 min.
tert-Butyl methyl 1-methyl-1,2-cyclopropanedicarboxylate (Entry 5, Table 1) was synthesized from methyl methacrylate with t-BDA. trans-isomer: 1H NMR (300 MHz, CDC13): δ3.69 (s, 3H), 2.23-2.28 (m, 1H), 1.49-1.52 (m, 1H), 1.46 (s, 9H), 1.39 (s, 3H), 1.24-1.27 (m, 1H). 13C NMR (75 MHz, CDC13): δ174.2, 169.5, 81.1, 52.3, 28.3, 28.1, 26.5, 20.6, 12.9. IR (film, cm−1): 1725 (C═O). HRMS (ESI): Calcd. for C11H22O4N ([M+NH4]+) m/z 232.1549. Found 232.1541. HPLC analysis: Whelk-O1 (98% hexanes: 2% isopropanol, 1.0 mL/min) trans-isomer: tmajor=7.01 min, tminor=7.57 min.
Ethyl 2-aminocarbonyl-cyclopropanecarboxylate (Kennewell et al., J. Chem. Soc., Perkin Trans. 1, 1982, 11, 2563.) (Entry 6, Table 1) was synthesized from acrylamide with EDA. trans-isomer: 1H NMR (300 MHz, CDC13): δ5.80 (br, 2H), 4.15 (q, J=7.2 Hz, 2H), 2.14-2.20 (m, 1H), 1.99-2.05 (m, 1H), 1.43-1.49 (m, 1H), 1.33-1.38 (m, 1H), 1.28 (t, J=7.2 Hz, 3H). 13C NMR (75 MHz, CDC13): δ172.5, 61.1, 23.4, 21.9, 15.0, 14.2. IR (film, cm−1): 3202-3420 (NH), 1721 (C═O), 1669 (C═O), 1622 (C═O). HRMS (ESI): Calcd. for C7H12NO3 ([M+H]+) m/z 158.0817. Found 158.0813. GC analysis: CP-Chirasil-Dex CB (Temp program: initial temp=50° C., 10.00° C./min, final temp=200° C., final time=10.00 min) trans-isomer: tmajor=17.36 min, tminor=17.42 min.
tert-Butyl 2-aminocarbonyl-cyclopropanecarboxylate (Entry 7, Table 1) was synthesized from acrylamide with t-BDA. trans-isomer: 1H NMR (300 MHz, CDC13): δ6.08 (br, 2H), 2.04-2.10 (m, 1H), 1.93-1.99 (m, 1H), 1.45 (s, 9H), 1.32-1.41 (m, 1H), 1.26-1.30 (m, 1H). 13C NMR (75 MHz, CDC13): δ173.2, 171.7, 81.2, 28.0, 23.1, 22.9, 14.8. IR (film, cm−1): 3205-3421 (NH), 1717 (C═O), 1671 (C═O), 1623 (C═O). HRMS (ESI): Calcd. for C9H19N2O3 ([M+NH4]+) m/z 203.1396. Found 203.1389. GC analysis: CP-Chirasil-Dex CB (Temp program: initial temp=50° C., 10.00° C./min, final temp=200° C., final time=10.00 min) trans-isomer: tminor=17.59 min, tmajor=17.76 min.
Ethyl 2-dimethylaminocarbonyl-cyclopropanecarboxylate (Entry 8, Table 1) was synthesized from N,N-dimethylacrylamide with EDA. trans-isomer: 1H NMR (300 MHz, CDC13): δ4.15 (q, J=7.2 Hz, 2H), 3.18 (s, 3H), 2.97 (s, 3H), 2.29-2.36 (m, 1H), 2.14-2.20 (m, 1H), 1.40-1.48 (m, 1H), 1.31-1.37 (m, 1H), 1.27 (t, J=7.2 Hz, 3H). 13C NMR (75 MHz, CDC13): δ172.8, 170.0, 60.7, 37.1, 35.7, 21.6, 20.8, 15.1, 14.0. IR (film, cm−1): 3490 (NH), 1725 (C═O), 1642 (C═O). HRMS (ESI): Calcd. for C9H15NO3Na ([M+Na]+) m/z 208.0950. Found 208.0942. HPLC analysis: Chiralcel OD-H (90% hexanes: 10% isopropanol, 1.0 mL/min) trans-isomer: tmajor=10.67 min, tminor=11.78 min.
tert-Butyl 2-dimethylaminocarbonyl-cyclopropanecarboxylate (Entry 9, Table 1) was synthesized from N,N-dimethylacrylamide with t-BDA. trans-isomer: 1H NMR (300 MHz, CDC13): δ3.17 (s, 3H), 2.97 (s, 3H), 2.22-2.28 (m, 1H), 2.07-2.13 (m, 1H), 1.45 (s, 9H), 1.35-1.40 (m, 1H), 1.26-1.32 (m, 1H). 13C NMR (75 MHz, CDC13): δ172.1, 170.4, 80.9, 37.2, 35.8, 28.0, 22.7, 20.7, 15.0. IR (film, cm−1): 3492 (NH), 1723 (C═O), 1645 (C═O). HRMS (ESI): Calcd. for C11H20NO3 ([M+H]+) m/z 214.1443. Found 214.1441. GC analysis: CP-Chirasil-Dex CB (Temp program: initial temp=50° C., 10.00° C./min, final temp=200° C., final time=10.00 min) trans-isomer: tminor=16.05 min, tmajor=16.12 min.
tert-Butyl 2-isopropylaminocarbonyl-cyclopropanecarboxylate (Entry 10, Table 1) was synthesized from N-isopropylacylamide with t-BDA. trans-isomer: 1H NMR (300 MHz, CDC13): δ5.81 (br, 1H), 4.03-4.10 (m, 1H), 2.03-2.09 (m, 1H), 1.78-1.84 (m, 1H), 1.45 (s, 9H), 1.33-1.39 (m, 1H), 1.20-1.25 (m, 1H), 1.18 (d, J=4.2 Hz, 3H), 1.15 (d, J=4.5 Hz, 3H). 13C NMR (75 MHz, CDC13): δ172.0, 169.4, 80.9, 41.7, 28.0, 24.0, 22.7, 22.3, 14.5. IR (film, cm−1): 3292 (NH), 1724 (C═O), 1643 (C═O). HRMS (ESI): Calcd. for C12H22NO3 ([M+H]+) m/z 228.1600. Found 228.1590. GC analysis: CP-Chirasil-Dex CB (Temp program: initial temp=50° C., 5.00° C./min, final temp=200° C., final time=10.00 min) trans-isomer: tminor=28.15 min, tmajor=28.26 min.
Ethyl 2-propionyl-cyclopropanecarboxylate (Hammerschmidt et al., Annalen der Chemie, 1977, 6, 1026.) (Entry 11, Table 1) was synthesized from ethyl vinyl ketone with EDA. trans-isomer: 1H NMR (300 MHz, CDC13): δ4.15 (q, J=7.2 Hz, 2H), 2.64 (q, J=7.2 Hz, 2H), 2.44-2.48 (m, 1H), 2.14-2.29 (m, 1H), 1.39-1.43 (m, 2H), 1.27 (t, J=7.2 Hz, 3H), 1.08 (t, J=7.2 Hz, 3H). 13C NMR (75 MHz, CDC13): δ208.1, 172.2, 61.0, 37.1, 28.7, 23.9, 17.0, 14.1, 7.6. IR (film, cm−1): 1729 (C═O), 1707 (C═O). HRMS (ESI): Calcd. for C9H15O3 ([M+H]+) m/z 171.1021, Found 171.1016. GC analysis: CP-Chirasil-Dex CB (Temp program: initial temp=50° C., Rate1: 3.00° C./min, max temp=100° C.; Rate2: 2.00° C./min, max temp=130° C.; Rate3: 10.00° C./min, max temp=200° C.; final time=5.00 min) trans-isomer: tmajor=26.42 min, tminor=26.84 min.
tert-Butyl 2-propionyl-cyclopropanecarboxylate (Entry 12, Table 1) was synthesized from ethyl vinyl ketone with t-BDA. trans-isomer: 1H NMR (300 MHz, CDC13): δ2.64 (q, J=7.2 Hz, 2H), 2.35-2.41 (m, 1H), 2.06-2.12 (m, 1H), 1.45 (s, 9H), 1.32-1.37 (m, 2H), 1.09 (t, J=7.2 Hz, 3H). 13C NMR (75 MHz, CDC13): δ208.3, 171.2, 81.1, 37.0, 28.5, 28.0, 25.0, 16.9, 7.6. IR (film, cm−1): 1707 (C═O). HRMS (ESI): Calcd. for C11H22O3N ([M+NH4]+) m/z 216.1600. Found 216.1592. GC analysis: CP-Chirasil-Dex CB (Temp program: initial temp=50° C., Rate1: 3.00° C./min, max temp=100° C.; Rate2: 2.00° C./min, max temp=130° C.; Rate3: 10.00° C./min, max temp=200° C.; final time=5.00 min) trans-isomer: tminor=30.11 min, tmajor=30.40 min.
Ethyl 2-hexanoyl-cyclopropanecarboxylate (Ornstein et al., J. Med. Chem. 1998, 41, 346.) (Entry 13, Table 1) was synthesized from 1-octen-3-one with EDA. trans-isomer: 1H NMR (300 MHz, CDC13): δ4.13 (q, J=7.2 Hz, 2H), 2.59 (t, J=7.2 Hz, 2H), 2.41-2.47 (m, 1H), 2.12-2.18 (m, 1H), 1.56-1.66 (m, 2H), 1.39-1.43 (m, 2H), 1.26-1.33 (m, 4H), 1.27 (t, J=7.2 Hz, 3H), 0.89 (t, J=6.9 Hz, 3H). 13C NMR (75 MHz, CDC13): δ207.7, 172.1, 60.9, 43.9, 31.3, 28.8, 23.9, 23.4, 22.3, 17.0, 14.1, 13.8. IR (film, cm−1): 1731 (C═O), 1706 (C═O). HRMS (ESI): Calcd. for C12H20O3Na ([M+Na]+) m/z 235.1310, Found 235.1305. GC analysis: CP-Chirasil-Dex CB (Temp program: initial temp=50° C., Rate1: 5.00° C./min, max temp=100° C.; Rate2: 0.90° C./min, max temp=140° C.; Rate3: 10.00° C./min, max temp=200° C.; final time=5.00 min) trans-isomer: tmajor=46.87 min, tminor=47.39 min.
tert-Butyl 2-hexanoyl-cyclopropanecarboxylate (Entry 14, Table 1) was synthesized from 1-octen-3-one with t-BDA. trans-isomer: 1H NMR (300 MHz, CDC13): δ2.59 (t, J=7.5 Hz, 2H), 2.34-2.40 (m, 1H), 2.04-2.10 (m, 1H), 1.56-1.66 (m, 2H), 1.45 (s, 9H), 1.25-1.35 (m, 6H), 0.90 (t, J=6.9 Hz, 3H). 13C NMR (75 MHz, CDC13): δ208.0, 171.2, 81.0, 43.8, 31.3, 28.6, 28.0, 25.0, 23.4, 22.4, 16.8, 13.8. IR (film, cm−1): 1707 (C═O). HRMS (ESI): Calcd. for C14H24O3Na ([M+Na]+) m/z 263.1623. Found 263.1616. GC analysis: CP-Chirasil-Dex CB (Temp program: initial temp=50° C., Rate1: 5.00° C./min, max temp=100° C.; Rate2: 2.00° C./min, max temp=150° C.; Rate3: 10.00° C./min, max temp=200° C.; final time=5.00 min) trans-isomer: tminor=37.71 min, tminor=37.91 min.
tert-Butyl 2-acetyl-2-methyl-cyclopropanecarboxylate (Entry 15, Table 1) was synthesized from 3-methyl-3-buten-2-one with t-BDA. trans-isomer: 1H NMR (300 MHz, CDC13): δ2.20-2.25 (m, 1H), 2.21 (s, 3H), 1.48 (s, 3H), 1.42-1.50 (m, 1H), 1.46 (s, 9H), 1.24-1.27 (m, 1H). 13C NMR (75 MHz, CDC13): δ207.5, 169.5, 81.1, 33.6, 30.0, 28.1, 26.8, 21.7, 13.6. IR (film, cm−1): 1728 (C═O). HRMS (ESI): Calcd. for C11H22O3N ([M+NH4]+) m/z 216.1600. Found 216.1588. GC analysis: CP-Chirasil-Dex CB (Temp program: initial temp=50° C., 4.00° C./min, final temp=200° C., final time=10.00 min) trans-isomer: tminor=22.80 min, tmajor=22.91 min.
Ethyl 2-cyanocyclopropanecarboxylate (Ashton et al., J. Med. Chem. 1988, 31, 2304.) (Entry 16, Table 1) was synthesized from acrylonitrile with EDA. trans-isomer: 1H NMR (300 MHz, CDC13): δ4.19 (q, J=7.2 Hz, 2H), 2.23-2.30 (m, 1H), 1.91-1.98 (m, 1H), 1.48-1.56 (m, 2H), 1.30 (t, J=7.2 Hz, 3H). 13C NMR (75 MHz, CDC13): δ170.1, 119.2, 61.7, 21.0, 14.4, 14.1, 5.6. IR (film, cm−1): 2245 (CN), 1730 (C═O). HRMS (ESI): Calcd. for C7H13N2O2 ([M+NH4]+) m/z 157.0977. Found 157.0972. cis-isomer: 1H NMR (300 MHz, CDC13): δ4.26 (q, J=7.2 Hz, 2H), 2.09-2.16 (m, 1H), 1.81-1.89 (m, 1H), 1.66-1.72 (m, 1H), 1.38-1.46 (m, 1H), 1.32 (t, J=7.2 Hz, 3H). 13C NMR (75 MHz, CDC13): δ168.8, 100.1, 61.7, 20.0, 14.1, 13.2, 5.6. IR (film, cm−1): 2245 (CN), 1730 (C═O). HRMS (ESI): Calcd. for C7H13N2O2 ([M+NH4]+) m/z 157.0977. Found 157.0972. GC analysis: G-TA (Temp program: initial temp=50° C., 10.00° C./min, final temp=180° C., final time=10.00 min) trans-isomer: tmajor=11.69 min, tminor=11.83 min; cis-isomer: tminor=14.74 min, tmajor=15.15 min.
tert-Butyl 2-cyanocyclopropanecarboxylate (Jonczyk A., Makosza M., Synthesis 1976, 6, 387.) (Entry 17, Table 1) was synthesized from acrylonitrile with t-BDA. trans-isomer: 1H NMR (300 MHz, CDC13): δ2.14-2.21 (m, 1H), 1.83-1.90 (m, 1H), 1.38-1.50 (m, 2H), 1.46 (s, 9H). 13C NMR (75 MHz, CDC13): δ169.1, 119.5, 82.4, 27.9, 22.0, 14.3, 5.3. IR (film, cm−1): 2240 (CN), 1718 (C═O). HRMS (ESI): Calcd. for C9H17N2O2 ([M+NH4]+) m/z 185.1290. Found 185.1286. cis-isomer: 1H NMR (300 MHz, CDC13): δ1.98-2.05 (m, 1H), 1.72-1.81 (m, 1H), 1.58-1.66 (m, 1H), 1.51 (s, 9H), 1.31-1.39 (m, 1H). 13C NMR (75 MHz, CDC13): δ167.7, 117.8, 82.5, 27.9, 20.9, 12.9, 5.3. IR (film, cm−1): 2241 (CN), 1725 (C═O). HRMS (ESI): Calcd. for C9H17N2O2 ([M+NH4]+) m/z 185.1290, Found 185.1289. GC analysis: CP-Chirasil-Dex CB (Temp program: initial temp=50° C., 10.00° C./min, final temp=200° C., final time=10.00 min) trans-isomer: tmajor=12.92 min, tminor=13.06 min; cis-isomer: tminor=13.81 min, tmajor=13.90 min.
Ethyl 2-cyano-2-methylcyclopropanecarboxylate (Doyle M. P., Davidson J. G., J. Org. Chem. 1980, 45, 1538.) (Entry 18, Table 1) was synthesized from methacrylonitrile with EDA. trans-isomer: 1H NMR (300 MHz, CDC13): δ4.20 (q, J=7.2 Hz, 2H), 2.29-2.34 (m, 1H), 1.58-1.63 (m, 1H), 1.50 (s, 3H), 1.40-1.42 (m, 1H), 1.30 (t, J=7.2 Hz, 3H). 13C NMR (75 MHz, CDC13): δ168.6, 122.4, 61.5, 26.0, 19.7, 14.7, 14.1, 13.8. IR (film, cm−1): 2243 (CN), 1732 (C═O). cis-isomer: 1H NMR (300 MHz, CDC13): δ4.24 (q, J=7.2 Hz, 2H), 1.81-1.92 (m, 2H), 1.50 (s, 3H), 1.31 (t, J=7.2 Hz, 3H), 1.20-1.25 (m, 1H). 13C NMR (75 MHz, CDC13): δ168.8, 120.0, 61.7, 27.9, 21.8, 20.9, 14.2, 12.9. IR (film, cm−1): 2243 (CN), 1731 (C═O). HRMS (ESI): Calcd. for C8H15N2O2 ([M+NH4]+) m/z 171.1134. Found 171.1128. GC analysis: CP-Chirasil-Dex CB (Temp program: initial temp=50° C., 10.00° C./min, final temp=200° C., final time=10.00 min) trans-isomer: tminor=11.76 min, tmajor=11.87 min; cis-isomer: tminor=12.32 min, tmajor=12.59 min.
tert-Butyl 2-cyano-2-methylcyclopropanecarboxylate (Jonczyk A., Makosza M., Synthesis 1976, 6, 387.) (Entry 19, Table 1) was synthesized from methacrylonitrile with t-BDA. trans-isomer: 1H NMR (300 MHz, CDC13): δ2.21-2.26 (m, 1H), 1.52-1.58 (m, 1H), 1.50 (s, 3H), 1.47 (s, 9H), 1.33-1.37 (m, 1H). 13C NMR (75 MHz, CDC13): δ 167.6, 122.7, 82.2, 28.0, 27.2, 19.3, 14.6, 12.2. IR (film, cm−1): 2239 (CN), 1726 (C═O). HRMS (ESI): Calcd. for C10H19N2O2 ([M+NH4]+) m/z 199.1447, Found 199.1438. cis-isomer: 1H NMR (300 MHz, CDC13): δ1.73-1.81 (m, 2H), 1.50 (s, 9H), 1.47 (s, 3H), 1.13-1.17 (m, 1H). 13C NMR (75 MHz, CDC13): δ167.8, 120.2, 82.4, 28.9, 28.0, 21.8, 20.7, 13.4. IR (film, cm−1): 2243 (CN), 1726 (C═O). HRMS (ESI): Calcd. for C10H16NO2 ([M+H]+) m/z 182.1181. Found 182.1172. GC analysis: CP-Chirasil-Dex CB (Temp program: initial temp=50° C., 10.00° C./min, final temp=200° C., final time=10.00 min) trans-isomer: tminor=12.63 min, tmajor=12.70 min; cis-isomer: tminor=12.83 min, tmajor=12.92 min.
Tiethyl trans-1,2,3-cyclopanetricarboxylate (Kozhushkov et al., Synthesis 2003, 6, 956.) (Entry 20, Table 1) was synthesized from diethyl maleate with EDA. 1H NMR (300 MHz, CDC13): δ4.18 (q, J=7.2 Hz, 2H), 4.17 (q, J=7.2 Hz, 4H), 2.77 (t, J=5.7 Hz, 1H), 2.54 (d, J=5.1 Hz, 2H), 1.29 (t, J=7.2 Hz, 3H), 1.27 (t, J=7.2 Hz, 6H). 13C NMR (75 MHz, CDC13): δ170.1, 167.5, 61.6, 61.5, 28.4, 25.6, 14.0. IR (film, cm−1): 1731 (C═O). HRMS (ESI): Calcd. for C12H22O6N ([M+NH4]+) m/z 276.1447. Found 276.1435.
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